The protease-activated receptor 1 (PAR1) is a thrombin receptor which belongs to the class of G protein-coupled receptors (GCPR). PAR1 is expressed in various tissues, e.g., endothelial cells, smooth muscles cells, fibroblasts, neurons and human platelets. It is involved in cellular responses associated with hemostasis, proliferation, and tissue injury. PAR1 is known to be activated by proteases, notably by thrombin, by cleavage at Arg41 or by peptides that mimic the new N-terminus created when cleavage at Arg41 occurs. Such peptides are often referred to as Thrombin Receptor Activating Peptides (TRAP). Thrombin cleavage of PAR1 or treatment of cells with TRAP are generally proinflammatory and can often be deleterious to cells or animals.
Plasma Protein C is a serine protease zymogen and is known for its mild deficiency linked to venous thrombosis risk and severe deficiency linked to neonatal purpura fulminans. Activated Protein C (APC) exerts both anticoagulant activity via proteolytic inactivation of factors Va and VIIIa and cellular cytoprotective actions via direct initiation of cell signaling. Based on studies of engineered APC mutants and the use of genetically modified mice, APC's cell signaling actions are thought to drive murine APC's mortality reduction in sepsis models, neuroprotective actions in brain injury models, and nephroprotective effects in kidney injury models. These actions in vivo are generally suggested to involve multiple receptors (PAR1, endothelial protein C receptor (EPCR), PAR3, and CD11b), while in vitro studies implicate these receptors and potentially also other receptors (apoER2, beta1 and beta3 integrins, S1P1, and the angiopoietin/Tie-2 axis) for APC's cellular effects. Crosstalk among these receptors may permit a timely integration of APC-induced signaling which ultimately determines APC's effects on a specific cell and organ.
Modulation of PAR1-mediated signaling activities could have various therapeutic applications. There is a need in the art for better means for such therapeutic applications. The present invention addresses this and other related needs.